Rectal Neuroendocrine Neoplasms: Why Is There a Global Variation?

PURPOSE OF REVIEW: This review examines the variation in incidence of rectal neuroendocrine tumours across the globe. Rectal neuroendocrine tumours are a common type of gastrointestinal NET with an increasing incidence reported over the last 30 years. RECENT FINDINGS: There have been a number of publications examining the epidemiology of neuroendocrine tumours across the world. These have utilized a variety of different methodologies to examine both incidence of prevalence of NETs. We review the data published and describe any causative factors and findings regarding the epidemiology of rectal NETs. Rectal NETs account for 1-2% of all rectal cancers and are commonly diagnosed between 50-60 years of age. Most lesions are identified by chance at colonoscopy, commonly during colon cancer screening procedures, which is reflected in part in the age at diagnosis. Most lesions are small in size, < 10 mm and can be managed with endoscopic resection rather than requiring surgery. The highest incidence is reported in people of Asian ethnicity, with a tenfold increased incidence reported in some series compared with white population. There is also an increased incidence in Black and Hispanic population as identified through the Surveillance, Epidemiology and End Results (SEER) database. Endoscopic assessment of lesions is variable globally. Future work to better understand the cause of ethnic variation and development of comprehensive cancer registries would be helpful.

Lessons from a multicentre retrospective study of peptide receptor radionuclide therapy combined with lanreotide for neuroendocrine tumours: a need for standardised practice.

PURPOSE: PRELUDE aimed to assess use and effectiveness/safety of lanreotide autogel/depot (LAN) combined with 177Lu-DOTATOC or 177Lu-DOTATATE (LAN-peptide receptor radionuclide therapy [PRRT]) in patients with progressive neuroendocrine tumours (NETs). METHODS: International, non-interventional, retrospective, non-comparative analysis of medical records from patients with progressive metastatic or locally advanced grade 1 or 2 gastroenteropancreatic (GEP)- or lung-NETs. The primary endpoint was progression-free survival (PFS) at end of last LAN-PRRT cycle. Secondary endpoints included PFS at last available follow-up, best overall response, objective response rate (ORR), presence and severity of diarrhoea and flushing, and safety. Post-hoc analyses were conducted to determine pre-treatment tumour growth rate (TGR) cutoffs that best predicted the ORR during treatment. RESULTS: Forty patients were enrolled (GEP-NETs, n = 39; lung-NETs, n = 1). PFS rates were 91.7% at end of last LAN-PRRT cycle and 95.0% at last available follow-up. In the full analysis set, best overall response among patients with GEP-NETs (n = 23) was stable disease (n = 14, 60.9%), partial response (n = 8, 34.8%) and progressive disease (n = 1, 4.3%). The ORR was 27.3% at end of last LAN-PRRT cycle and 36.8% at last available follow-up. Optimal baseline TGR cutoffs for predicting ORR at these time points were 1.18% and 0.33%, respectively. At baseline, 81.0% of patients had diarrhoea or flushing; both remained stable or improved in most cases. No increased adverse drug reactions were reported. CONCLUSION: Despite the major recruitment shortfall for the PRELUDE study, effectiveness data were encouraging in this selected population, highlighting the potential usefulness and feasibility of LAN combined with and after PRRT in patients with GEP-NETs. The study also identified challenges associated with evaluating clinical practice in a rare-disease setting and highlighted the need for standardisation of PRRT procedures. TRIAL REGISTRATION: Trial number: NCT02788578; URL: https://clinicaltrials.gov/ct2/show/NCT02788578.

Lung Metastases in Patients with Well-Differentiated Gastroenteropancreatic Neuroendocrine Neoplasms: An Appraisal of the Validity of Thoracic Imaging Surveillance.

BACKGROUND/AIMS: To evaluate the impact of lung metastases (LM) on overall survival (OS) in well-differentiated (WD) stage IV gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) patients along with developing surveillance strategies for thoracic imaging. METHODS: Thirty-four patients with LM, from 3 centres, were identified (22 small intestine/12 pancreatic; 17 grade 1/15 grade 2/2 of unknown grade). For comparison, we used 106 stage IV WD, grade 1 and 2 GEP-NEN patients with metastatic disease confined in the abdomen. RESULTS: LM prevalence was 4.9% (34/692). Eleven patients (32%) presented with synchronous LM whereas 23 (68%) developed metachronous LM at a median of 25 months (range 1-150 months). Patients with metachronous LM had already established liver and/or para-aortic lymph node metastases. Eighteen of 23 patients (78%) with metachronous LM exhibited concomitant progression in the abdomen. Median OS of WD GEP-NEN patients with LM was shorter than for those with stage IV disease without extra-abdominal metastases (56 [95% CI 40.6-71.6] vs. 122.7 [95% CI 70.7-174.8] months; log-rank p = 0.001). Among patients with progressive stage IV disease, the subset of patients with LM exhibited shorter OS (log-rank p = 0.005). LM were also confirmed as an independent prognostic factor for survival in multivariable analysis (HR 0.18; 95% CI 0.07-0.45; p < 0.0001). CONCLUSION: LM, although relatively rare in patients with WD stage IV GEP-NENs, may impact patients' outcome. The development of metachronous LM is associated with concomitant disease progression in established abdominal metastases in most patients. These patient-related parameters could be utilized for a stratified surveillance approach, mainly reserving thoracic imaging for GEP-NEN patients with progressive disease in the abdomen.

Delays and routes to diagnosis of neuroendocrine tumours.

BACKGROUND: Neuroendocrine tumours are uncommon tumours; there is often a long period between the onset of symptoms and diagnosis. This study aims to address the symptoms prior to diagnosis of people with known neuroendocrine tumours and also the involvement of healthcare providers prior to the diagnosis. METHODS: A web based survey was designed to cover two broad areas of patient symptoms and healthcare interactions prior to diagnosis. This was tested and adapted by patient and clinician input prior to distribution via Survey Monkey. RESULTS: The results demonstrated a median time from first symptom to diagnosis of 53.8 months. The most frequent initial symptoms were of pain, change in bowel habit and fatigue. 31% of respondents noted weight loss prior to diagnosis. 80% of respondents visited their GP regarding the symptoms a median of 11 times. 58% of respondents were referred to secondary care where they were seen a median 3 times. 30% presented acutely to A&E and this led to their diagnosis. CONCLUSION: In conclusion, there is a long time from onset of symptoms to diagnosis in all types of NETs. This is despite many respondents having alarm symptoms at diagnosis. Further education and awareness regarding malignancy may help with earlier diagnosis.

Presenting Symptoms and Delay in Diagnosis of Gastrointestinal and Pancreatic Neuroendocrine Tumours.

The gastrointestinal tract and pancreas are common primary sites for neuroendocrine tumours (NETs). Patients often report a long duration of non-specific symptoms in the year prior to diagnosis. The aims of this study were, firstly, to establish pre-diagnosis patterns of symptoms, and secondly, to determine the time from onset of symptoms to NET diagnosis and understand the interaction with primary and secondary healthcare providers. A survey was designed on a web-based survey platform with the focus on patient symptoms prior to diagnosis and a screen for functional diarrhoea (Rome III criteria [C4]). A total of 303 responses were received. The median duration from the time of first symptoms to diagnosis was 36 months for small bowel NETs and 24 months for pancreatic NETs. Common first symptoms were pain (36%), flushing (24%), and diarrhoea (24%); 29% of small bowel NET respondents were given an initial diagnosis of irritable bowel syndrome. Dyspepsia was the second most common initial incorrect diagnosis. Respondents saw their GP 5 times over a median 18-month period for their symptoms; 31% of patients were diagnosed following unplanned emergency admission. In conclusion, this survey demonstrates a median time to diagnosis of 36 months for patients with small bowel NETs. Incorrect initial diagnosis appears to be very common, with a high number of attendances in primary and secondary care prior to a correct diagnosis being made. An earlier diagnosis may improve patients' quality of life and possible survival.

Optimized Outcomes Using a Standardized Approach for the Treatment of Patients with Carcinoid Heart Disease.

BACKGROUND: Carcinoid heart disease (CHD) is common in patients with carcinoid syndrome (CS). Surgical treatment improves the poor prognosis of CHD, although the reported peri-operative mortality is high (∼17%). We attempted to improve outcomes by implementation of a protocol for the management of patients with CHD at a UK Neuroendocrine Centre of Excellence and report our experience. METHODS: All patients treated for CHD between 2008 and 2015 were included. Peri-operative treatment included surgical features such as invasive pulmonary valve (PV) inspection and preservation of the tricuspid subvalvular apparatus. RESULTS: A total of 11 patients were treated; the median age was 63 years (IQR: 56-70). Ten patients underwent both pulmonary valve replacement (PVR) and tricuspid valve replacement (TVR); 1 patient underwent isolated TVR. One patient had additional aortic valve replacement (AVR), another one coronary artery bypass grafting. Bioprostheses (BP) were used in all patients, stented for TVR and AVR, stentless for PVR. Invasive PV inspection caused unplanned PVR in 3 cases (27.3%). All patients were discharged home. One patient (9.1%), who had had previous TVR by another surgeon, had right heart failure (RHF) during follow-up. One death occurred due to progression of CS (day 346). The carcinoids' primary was resected in 5 patients (45.5%) 10 months (4.5-19.5) after cardiac surgery. CONCLUSION: Excellent results were achieved in patients with CHD. PV stenosis can be underestimated by echocardiography; therefore, intraoperative inspection is recommended. Right ventricular geometry should be respected to prevent RHF. BP should be used, as these patients are likely to undergo future non-cardiac surgeries.

Modified Histopathological Grading Optimizes Prediction of Survival Outcomes in Small Intestinal Neuroendocrine Tumours.

CONTEXT: One of the major prognostic indices in neuroendocrine tumours (NETs) is Ki67 proliferation index. OBJECTIVE: To identify optimal grading Ki-67 cut-offs to delineate differences in prognosis of patients with small intestinal NETs (SI-NETs). DESIGN, SETTING, PARTICIPANTS: Multicentre retrospective cohort analysis of 551 SI-NET patients diagnosed from 1993 through 2021 at five European referral centres with a mean(±SD) follow-up time of 51.5(±52.9) months. MAIN OUTCOME MEASURES: Overall- and event-free survival (OS and EFS) rates. RESULTS: Median age at baseline was 62.3(range:17-90) years; 252(45.7%) patients were female. All SI-NETs were well-differentiated with 326 being grade 1(G1; 59.2%), 169G2(30.7%), and only 8G3(1.5), while 48 tumours were of unspecified grade (8.7%). The median Ki67 was 2%(range:1-70%). Two-hundred forty-seven patients (44.8%) had distant metastases at baseline (stage IV), 217 locoregional disease (41.1%; stage III), whereas 29(7.1%) and 25(4.5%) presented at stages II and I, respectively. The median OS was 214.7(95%CI:152.7-276.6) months and the median EFS was 79.8(95%CI:68.2-91.5) months, respectively. In multivariable Cox-regression OS analysis, the proposed modified histopathological Ki67 grading system (K67:5-10% group: HR=2.2, 95%CI:1.15-4.31; p=0.018 and K67≥10% group: HR=5.11, 95%CI:2.87-9.09; p<0.001), age (HR=1.07, 95%CI:1.04-1.09; p<0.001), Charlson Comorbidity Index (HR=1.08, 95%CI:1-1.16; p=0.028) and TNM stage (HR=1.79, 95%CI:1.05-3.06; p=0.034) were independent predictors for death. Pertinent EFS analysis, confirmed the proposed modified histopathological Ki67 grading system (K67≥10% group: HR=4.01, 95%CI:2.6-6.37; p<0.001) and age (HR=1.04, 95%CI:1.02-1.05; p<0.001) as independent predictors for recurrence, progression and/or death. CONCLUSIONS: Ki-67 proliferation index was a strong and independent predictor of OS and EFS. A modified histopathological grading system applying Ki-67 cut-offs of 5 and 10% could be superior to predict differences in SI-NET patient survival outcomes.

Neuroendocrine neoplasms: Consensus on a patient care pathway.

People with neuroendocrine neoplasms (NENs) face a multitude of challenges, including delayed diagnosis, low awareness of the cancer among healthcare professionals and limited access to multidisciplinary care and expert centres. We have developed the first patient care pathway for people living with NENs in England to guide disease management and help overcome these barriers. The pathway was developed in two phases. First, a pragmatic review of the literature was conducted, which was used to develop a draft patient care pathway. Second, the draft pathway was then updated following semi-structured interviews with carefully selected expert stakeholders. After each phase, the pathway was discussed among a multidisciplinary, expert advisory group (which comprised the authors and the Deputy Chief Operating Officer, West Suffolk NHS Foundation Trust), who reached a consensus on the ideal care pathway. This article presents the outputs of this research. The pathway identified key barriers to care and highlighted how these may be addressed, with many of the findings relevant to the rest of the UK and international audiences. NENs are increasing in incidence and prevalence in England, compounding pre-existing inequities in diagnosis and disease management. Effective integration of this pathway within NHS England will help achieve optimal, equitable care provision for all people with NENs, and should be feasible within the existing expert multidisciplinary teams across the country.

Real-world data evaluating Guy's rapid diagnostic clinic as an alternate pathway for patients with FIT levels below 10.

OBJECTIVE: To analyse the effectiveness of rapid diagnostic clinics (RDCs) as an alternative pathway for patients with concerning symptoms and a faecal immunochemical test (FIT) result <10. Our primary endpoint was rate of colorectal cancer (CRC) detection. Second endpoints were rates of other cancers and gastrointestinal (GI) serious benign conditions. Finally, we analysed the specific pathway followed by FIT <10 patients with cancer at Guy's and St Thomas NHS Foundation Trust (GSTT) RDC. DESIGN: A retrospective and prospective cohort study. SETTING: GSTT RDC, one of England's largest single-centre RDCs. Sociodemographic and clinical characteristics of FIT <10 patients were analysed descriptively. PARTICIPANTS: Patients with an FIT result <10, seen at GSTT RDC between 1 January 2020 and 5 May 2023. RESULTS: A total of 1299 patients with an FIT<10 were seen at GSTT RDC between January 2020 and May 2023. Of these, 66% (n=861) reported weight loss, 62% (n=805) pain, 37% (n=481) fatigue, 34% (n=444) were anaemic and 23% (n=301) had nausea and vomiting. Among these patients, 7% (n=88) received a cancer diagnosis, 36% (n=462) were identified as having a serious benign condition. Within the patients with cancer, 9% (n=8) were diagnosed with CRC. Among patients with serious benign conditions, 7% (n=31) were referred to colorectal, hepatopancreatobiliary, or upper GI specialists. CONCLUSION: This study demonstrates the effectiveness of RDCs as an alternate pathway for FIT <10 patients with ongoing clinical concerns. These results contribute to enhancing patient care and optimising resource allocation within the healthcare system.

Diagnosis and management of neuroendocrine tumours.

Neuroendocrine tumours (NETs) represent a heterogenous group of tumours, with diversity in their primary tumour sites, functional status (ie hormone secreting or non-functional) and degrees of aggressiveness (ranging from well-differentiated, grade 1 neuroendocrine tumours to poorly differentiated grade 3, neuroendocrine carcinomas). The most common sites are the lung, small bowel, pancreas and appendix. Clinical presentation is variable, ranging from incidental lesions detected on cross-sectional imaging, small bowel obstruction, carcinoid syndrome or other syndromic presentations (eg hypoglycaemia resulting from insulinoma) through to florid carcinoid heart disease. Diagnosis relies on biochemical markers, computed tomography (CT), magnetic resonance imaging (MRI) and somatostatin-receptor based functional imaging. Treatment comprises surgery where curative resection is possible through to approaches where disease stabilisation is the key, involving somatostatin analogues, peptide receptor radionuclide therapy (PRRT), everolimus, sunitinib, liver-directed therapies and sometimes chemotherapy. Although local and systemic complications can occur, they are associated with reasonable 5- and 10-year survival rates, respectively.

Improving outcomes in carcinoid heart disease - learning from a single centre.

INTRODUCTION: A significant proportion of patients with carcinoid syndrome develop carcinoid heart disease (CHD). Valve degeneration can lead to right heart failure, and worsening prognosis. Replacement of affected valves is an effective therapy. We reviewed patients treated with valve replacement to assess prognostic factors. METHODS: CHD patients records who underwent valve replacement from 2003-2019 were reviewed. RESULTS: Twenty-six patients underwent valve replacement. Mean (SD) age was 61 (11) years, 54% female. Eleven tumours were grade G1, with the remaining G2. NYHA pre-surgery mean (SD) 2.0 (0.7); post-surgery mean 1.2; follow-up mean (SD) 1.6 (0.8). Mean NYHA score difference from pre- to post-surgery -0.71 ( P  = 0.002). 88.5% two (PR & TR), 3.9% one, 3.9% three and 3.9% four valves replaced. 13 patients received Lu177 oxodotreotide; 27% completed four cycles. Mortality at 1 and 5 years follow up was 42% and 50% respectively. Cox proportional hazards model of survival from surgery, adjusting for age [hazard ratio (HR) 0.96 (0.89-1.03) ( P  = 0.25)], four cycles of Lu177 oxodotreotide demonstrated HR 0.087 (0.0079-0.95) ( P  = 0.045) indicating improved survival. DISCUSSION: Surgical patients were often NYHA grade II, and symptoms improved post-surgery. Four cycles of Lu177 oxodotreotide improved survival, although the confidence interval was wide. Further studies should be performed to assess Lu177 oxodotreotide in CHD.

Pancreatic metastases in patients with neuroendocrine neoplasms: A multi-centre cohort study.

Pancreatic metastases (PMs) from neuroendocrine neoplasms (NENs) are rare but the increased sensitivity of new diagnostic tools such as 68 Ga-DOTATATE PET/CT has resulted in their increased recognition at initial diagnosis or follow-up. A retrospective analysis of the data of patients from six tertiary referral centres was performed in order to identify the characteristics and the prognostic significance of PMs in patients with NENs. We used a control group of 69 age-, sex- and primary tumour - matched NEN patients from the same cohort with stage IV disease but no PMs. Overall survival (OS) was assessed using the Kaplan-Meier method log-rank analysis was used to assess the impact of various clinical and histopathological variables in OS. We identified 25 patients (11 females) with PMs with a median age at diagnosis of 60 years. The small intestine was the most common primary (80%) with a prevalence of 4.2% PMs (21/506). Fourteen patients presented with synchronous PMs whereas 11 developed metachronous PMs after a median time of 28 months (range: 7-168 months). Grading was available in 24 patients; 16 patients had G1 tumours, four G2, two atypical lung carcinoid, one typical and one atypical thymic carcinoid. Most patients had other concomitant metastases (12 hepatic, 4 lung and 6 bone) while five patients exhibited peritoneal carcinomatosis. Median OS in the PMs group was not reached compared with 212 months in the control group (95% CI: 26-398). The univariate analysis identified no prognostic factors statistically significantly associated with the OS. In conclusion, PMs are encountered with a low prevalence among NEN patients mostly developing in patients with advanced metastatic disease. The presence of PMs does not seem to be associated with a negative prognostic impact in OS.

Duodenal neuroendocrine neoplasms with unexpectedly aggressive behaviour: Challenging the "watch and wait" approach.

The incidence of duodenal neuroendocrine neoplasms has risen over the past decades as a result of the wide availability of endoscopy and associated expertise. Although it is considered that tumour size greater than 10 mm, higher tumour grade and/or location in relation to the ampulla of Vater represent the main risk factors for local or distant metastases, we describe two cases of well differentiated grade 1 and grade 2 neuroendocrine tumours, which measured < 10 mm at the time of diagnosis but had an aggressive course during follow-up. Furthermore, we also summarise the available therapeutic strategies for the management of small, low grade, non-functioning, non-ampullary duodenal neuroendocrine neoplasms.

Association of lymph node metastases, grade and extent of mesenteric lymph node dissection in locoregional small intestinal neuroendocrine tumors with recurrence-free survival.

We aimed to assess the prognostic impact of tumor- and patient-related parameters in patients with stage I-III small intestinal neuroendocrine tumors (SI-NETs), who underwent locoregional resective surgery (LRS) with curative intent. We included 229 patients with stage I-III SI-NETs diagnosed from June 15, 1993, through March 8, 2021, identified using the SI-NET databases from five European referral centers. Mean ± SD age at baseline was 62.5 ± 13.6 years; 111/229 patients were women (49.3%). All tumors were well-differentiated; 160 were grade 1 (G1) tumors, 51 were G2, two were G3 and 18 tumors were of unspecified grade (median Ki-67: 2%, range 1%-50%). One-hundred and sixty-three patients (71.2%) had lymph node (LN) involvement. The median number of retrieved lymph nodes was 10 (0-63), whereas the median number of positive LNs was 2 (0-43). After a mean ± SD follow-up of 54.1 ± 64.1 months, 60 patients experienced disease recurrence at a median (range) of 36.2 (2.5-285.1) months. The 5- and 10-year recurrence-free survival (RFS) rates were 66.6% and 49.3% respectively. In univariable analysis, there was no difference in RFS and overall survival (OS) between LN-positive and LN-negative patients (log-rank, p = .380 and .198, respectively). However, in stage IIIb patients who underwent mesenteric lymph node dissection (MLND) with a minimum of five retrieved LN (n = 125), five or more LN metastases were associated with shorter RFS (median RFS [95% CI] = 107.4 [0-229.6] vs. 73.7 [35.3-112.1] months; log-rank, p = .048). In addition, patients with G2 tumors exhibited shorter RFS compared to patients with G1 tumors (median RFS [95% confidence interval (CI)] = 46.9 [36.4-57.3] vs. 120.7 [82.7-158.8] months; log-rank, p = .001). In multivariable Cox-regression RFS analysis in stage IIIb patients, the Ki-67 proliferation index (hazard ratio = 1.08, 95% CI = 1.035-1.131; p < .0001) and the number of LN metastases (hazard ratio = 1.06, 95% CI = 1.001-1.125; p = .047) were independent prognostic factors for RFS. In conclusion, LRS with a meticulous MLND and a minimum number of five harvested LNs appears to be critical in the surgical management of SI-NET patients with locoregional disease. In patients who underwent LRS and MLND, the Ki-67 proliferation index and the LN metastases count were independent predictors of RFS.

Development of a quality of life questionnaire for patients with pancreatic neuroendocrine tumours (the PANNET module).

Pancreatic neuroendocrine tumours (panNET) are heterogeneous neoplasms usually characterised by slow growth and secretion of hormones, which often cause symptoms. The effect of these symptoms on quality of life (QoL) has not previously been examined in detail. EORTC (European Organisation for Research and Treatment of Cancer) guidelines were followed in phases 1-3 to produce a potential module of questions usable for trials in panNET, focusing on three common types of panNET. For two less common types, a list of symptoms was constructed. Following an extensive literature search and phase 1a interviews with patients and healthcare workers, a long list of potential issues (169) was obtained. This list was shown to 12 patients from three countries in phase 1b interviews to check that no items were missed. The list was reduced to 57 issues. The list of issues was converted to questions, mainly from existing validated questions within the EORTC item library. The list of questions was then used in a phase 3 international study in eight countries using seven languages. A provisional module of 24 items is presented for use in nonfunctioning panNET, gastrinoma and insulinoma. This module increases knowledge concerning QoL in this condition and may be a useful adjunct in clinical trials. A phase 4 trial is being considered for validation of this questionnaire.

Is local excision sufficient in selected grade 1 or 2 type III gastric neuroendocrine neoplasms?

PURPOSE: Type III gastric neuroendocrine neoplasms (g-NENs) have historically been regarded as aggressive tumours, hence current guidelines advocate radical surgery with lymph node dissection. Data on the roles of endoscopic or less extensive surgical resections are more limited. The aim of our study is to evaluate the clinicopathological features and long-term outcomes of patients undergoing endoscopic or limited surgical resection for localised grade 1 or 2 type III g-NENs when compared to radical surgery. METHODS: Retrospective analysis of all patients diagnosed with a localised grade 1 or 2 type III g-NENs across six tertiary NEN centers between 2006 and 2019. RESULTS: Forty-five patients were diagnosed with a potentially resectable grade 1 or 2 type III g-NEN of whom 36 underwent either endoscopic or surgical resection. No statistically significant differences were found between the three resection groups in terms of patient age, tumour location, grade or size. Only tumour size was found to be significantly associated with poor clinical outcome (p = 0.012) and ROC curve analysis identified tumour size >10 mm as a negative predictor (AUC:0.8030, p = 0.0021). Tumours >10 mm were also more likely to be associated with lymph node metastases on imaging and histology (p = 0.039 and p = 0.026 respectively). CONCLUSIONS: Localised grade 1 or 2 type III g-NENs had a good prognosis in this series. Tumour size >10 mm was the most significant prognostic factor affecting patient outcome. Endoscopic resection or limited surgical resection is feasible and safe in small type III g-NENs which demonstrate favourable grade 1/2, well differentiated histology.

The Impact of 68Gallium DOTA PET/CT in Managing Patients With Sporadic and Familial Pancreatic Neuroendocrine Tumours.

Objective: Pancreatic neuroendocrine tumours (panNETs) arise sporadically or as part of a genetic predisposition syndrome. CT/MRI, endoscopic ultrasonography and functional imaging using Octreoscan localise and stage disease. This study aimed to evaluate the complementary role of 68Gallium (68Ga)-DOTA PET/CT in managing patients with panNETs. Design: A retrospective study conducted across three tertiary UK NET referral centres. Methods: Demographic, clinical, biochemical, cross-sectional and functional imaging data were collected from patients who had undergone a 68Ga-DOTA PET/CT scan for a suspected panNET. Results: We collected data for 183 patients (97 male): median (SD) age 63 (14.9) years, 89.1 vs. 9.3% (n=163 vs. 17) alive vs. dead (3 data missing), 141 sporadic vs. 42 familial (MEN1, n=36; 85.7%) panNETs. Non-functional vs. functional tumours comprised 73.2 vs. 21.3% (n=134 vs. 39) (10 missing). Histological confirmation was available in 89% of individuals (n=163) but tumour grading (Ki67 classiifcation) was technically possible only in a smaller cohort (n=143): grade 1, 50.3% (n=72); grade 2, 46.2% (n=66) and grade 3, 3.5% (n=5) (40 histopathological classification either not technically feasible or biopsy not perfomed). 60.1% (n=110) were localised, 14.2% (n=26) locally advanced and 23.5% (n=43) metastatic (4 missing). 224 68Ga-DOTA PET/CT scans were performed in total for: diagnosis/staging 40% (n=88), post-operative assessment/clinical surveillance 53% (n=117) and consideration of peptide receptor radionuclide therapy (PRRT) 8% (n=17) (2 missing). PET/CT results confirmed other imaging findings (53%), identified new disease sites (28.5%) and excluded suspected disease (5%). Overall, 68Ga-DOTA PET/CT imaging findings provided additional information in 119 (54%) patients and influenced management in 85 (39%) cases. Conclusion: 68Ga-DOTA PET/CT imaging more accurately stages and guides treatment in patients with sporadic/familial panNETs with newly diagnosed/recurrent disease.

Update on Pathophysiology, Treatment, and Complications of Carcinoid Syndrome.

Carcinoid syndrome (CS) develops in patients with hormone-producing neuroendocrine neoplasms (NENs) when hormones reach a significant level in the systemic circulation. The classical symptoms of carcinoid syndrome are flushing, diarrhoea, abdominal pain, and wheezing. Neuroendocrine neoplasms can produce multiple hormones: 5-hydroxytryptamine (serotonin) is the most well-known one, but histamine, catecholamines, and brady/tachykinins are also released. Serotonin overproduction can lead to symptoms and also stimulates fibrosis formation which can result in development of carcinoid syndrome-associated complications such as carcinoid heart disease (CaHD) and mesenteric fibrosis. Transforming growth factor beta (TGF-ß) is one of the main factors in developing fibrosis, but platelet-derived growth factor (PDGF), basic fibroblast growth factor (FGF2), and connective tissue growth factor (CTGF or CCN2) are also related to fibrosis development. Treatment of CS focuses on reducing serotonin levels with somatostatin analogues (SSA's). Telotristat ethyl and peptide receptor radionuclide therapy (PRRT) have recently become available for patients with symptoms despite being established on SSA's. Screening for CaHD is advised, and early intervention prolongs survival. Mesenteric fibrosis is often present and associated with poorer survival, but the role for prophylactic surgery of this is unclear. Depression, anxiety, and cognitive impairment are frequently present symptoms in patients with CS but not always part of their care plan. The role of antidepressants, mainly SSRIs, is debatable, but recent retrospective studies show evidence for safe use in patients with CS. Carcinoid crisis is a life-threatening complication of CS which can appear spontaneously but mostly described during surgery, anaesthesia, chemotherapy, PRRT, and radiological procedures and may be prevented by octreotide administration.

Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) ≤2 cm: Study Protocol for a Prospective Observational Study.

Introduction: The optimal treatment for small, asymptomatic, nonfunctioning pancreatic neuroendocrine neoplasms (NF-PanNEN) is still controversial. European Neuroendocrine Tumor Society (ENETS) guidelines recommend a watchful strategy for asymptomatic NF-PanNEN <2 cm of diameter. Several retrospective series demonstrated that a non-operative management is safe and feasible, but no prospective studies are available. Aim of the ASPEN study is to evaluate the optimal management of asymptomatic NF-PanNEN ≤2 cm comparing active surveillance and surgery. Methods: ASPEN is a prospective international observational multicentric cohort study supported by ENETS. The study is registered in ClinicalTrials.gov with the identification code NCT03084770. Based on the incidence of NF-PanNEN the number of expected patients to be enrolled in the ASPEN study is 1,000 during the study period (2017-2022). Primary endpoint is disease/progression-free survival, defined as the time from study enrolment to the first evidence of progression (active surveillance group) or recurrence of disease (surgery group) or death from disease. Inclusion criteria are: age >18 years, the presence of asymptomatic sporadic NF-PanNEN ≤2 cm proven by a positive fine-needle aspiration (FNA) or by the presence of a measurable nodule on high-quality imaging techniques that is positive at 68Gallium DOTATOC-PET scan. Conclusion: The ASPEN study is designed to investigate if an active surveillance of asymptomatic NF-PanNEN ≤2 cm is safe as compared to surgical approach.